Reversal of dopamine D-2 receptor responses by an anandamide transport inhibitor

We characterized the pharmacological properties of the anandamide transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) in rats and investiga ted the effects of this drug on behavioral responses associated with activa tion of dopamine D-2 family receptors. Rat brain slices accumulated [H-3] a nandamide via a high-affinity transport mechanism that was blocked by AM404 . When administered alone in vivo, AM404 caused a mild and slow-developing hypokinesia that was significant 60 min after intracerebroventricular injec tion of the drug and was reversed by the CB1 cannabinoid receptor antagonis t SR141716A. AM404 produced no significant catalepsy or analgesia, two typi cal effects of direct-acting cannabinoid agonists. However, AM404 prevented the stereotypic yawning produced by systemic administration of a low dose of apomorphine, an effect that was dose-dependent and blocked by SR141716A. Furthermore, AM404 reduced the stimulation of motor behaviors elicited by the selective D-2 family receptor agonist quinpirole. Finally, AM404 reduce d hyperactivity in juvenile spontaneously hypertensive rats, a putative mod el of attention deficit hyperactivity disorder. The results support a prima ry role of the endocannabinoid system in the regulation of psychomotor acti vity and point to anandamide transport as a potential target for neuropsych iatric medicines.